(a) Field of the Invention
The present invention relates to a method for obtaining highly pure amorphous, anhydrous crystalline, or hydrated crystalline docetaxel with a high conversion rate and a high yield by solvent precipitation, colloid formation, etc., using several solvents.
(b) Description of the Related Art
Docetaxel has been used as one of the important anticancer agents together with paclitaxel. Docetaxel is semi-synthesized by obtaining its precursors such as 10-deacetylbaccatin III, baccatin III, etc., from the leaves and stems of yew and converting them into docetaxel by chemical reactions.
Like paclitaxel, docetaxel shows very low solubility in most pharmaceutical solvents including water, and accordingly there are numerous restrictions on its formulation and prescription.
The solubility of a material is influenced by its solid-state properties, and it has been suggested that the solubility of an amorphous structure is 10 times to 1600 times higher than that of its most stable crystalline structures (Bruno C. Hancock and Michael Parks, What is the true solubility advantage for amorphous pharmaceuticals. Pharmaceutical Res. 2000, 17, 397-404). This indicates that while solubility against a specific solvent is largely determined by the properties of the materials themselves, it can be improved by altering the configuration of the materials. Besides the change in the configuration of materials, solubility and dissolution rate can be improved by making the particle size of the materials small, thereby enlarging their surface area. On the other hand, in the case that the configuration of particles is amorphous, in general, their stability is decreased over storage time when compared with crystalline structures. Korean Patent No. 10-0391753 by Jacques Doveze, et al. discloses that docetaxel hydrate is more stable than its anhydrate.
Accordingly, as the properties of docetaxel vary by its final morphologies including amorphous form, crystalline form, hydrate, and anhydrate, there is a need to selectively obtain it having a suitable morphology according to its intended use. So far, however, there have been few known methods of selectively obtaining docetaxel having a specific morphology.
Recently, due to the stability of hydrates, there has been increasing interest in methods for the preparation of docetaxel hydrate. Jacques Doveze, et al., describes in Korean Patent No. 10-0391753 that docetaxel trihydrate is obtained by crystallizing docetaxel from a mixture of water and aliphatic alcohol having 1 to 3 carbon atoms and drying the obtained products at a temperature of about 40° C. and a reduced pressure of 4 to 7 kPa, in a humid atmosphere where the relative humidity is controlled to about 80%. The method proposed therein comprises crystallization and hydration steps. In the crystallization step, docetaxel is dissolved in aliphatic alcohols having 1 to 3 carbon atoms preferably at temperatures of 40 to 60° C., to which purified water is then added at the same temperature and then cooled to produce crystals. In the embodiment, it is described that 303 g of docetaxel was heated to 50° C. until it was completely dissolved in 0.983 L of ethanol, and while the temperature of 50° C. was being maintained, 4.39 L of purified water was added thereto over 1 hour. Such a crystallization process, however, requires heating for at least 1 hour up to high temperatures under the solvents and there arises the problem that docetaxel may be degraded due to its instability. Although it showed that the titer of the specimen used in the embodiment was improved to 98.7% from its initial 92.4% through crystallization, the degraded matter from the crystallization process may be included in the included impurities. Therefore, it would have been advisable for the described embodiment to evaluate and compare the impurities occurring during the processes using docetaxel with a high purity of as high as 99.5% because it was the final step of the manufacturing processes for determining the morphology of the final products. Thus, there is a limit in that it ignored evaluation of degradation products that could be generated during the crystallization process by using a specimen having low titer.
Arun Prakash Sharma, et al., disclose in U.S. Pat. No. 6,838,569 a process for the purification of paclitaxel and docetaxel trihydrates. In the above process, partially purified docetaxel is purified under the conditions of alkane-chloroalkane, acetone-hexane into a chromatography purity of 99.53%, which is then crystallized using acetonitrile and water. After the purified docetaxel is dissolved in acetonitrile at 50 to 70° C., to which purified water is slowly added, it is subjected to additional agitation at 15 to 20° C., to thereby obtain precipitates. The process disclosed in the above patent, although it did not mention dissolution time, cannot avoid the degradation of docetaxel by warming it to 50 to 70° C. even though there was little change in purity before and after crystallization. Moreover, as the applied process is the final purification step, recovery rate can be a very essential factor. The embodiment of this patent showed that 415 g of trihydrate (moisture 6.8%) was obtained from 460 g of anhydrate prior to crystallization, but in consideration of moisture, actual yield corresponds to approximately 84% which is considered to be comparatively low. This is one of the drawbacks that can be seen in common re-crystallization.
Li Jinliang, et al., discloses in International Patent Publication WO2004/099167 a method for the preparation of trihydrate by crystallizing anhydrous docetaxel in a mixed solution of purified water and acetone. In the embodiment, 87 g of anhydrate was dissolved in acetone, to which purified water at 1.5 times thereof was then added, and it was then crystallized at 0° C. for two days to thereby prepare 85 g of trihydrate (moisture 6.43%). However, this method is also a common re-crystallization method, and actual recovery rate is as low as 91% in consideration of moisture amount.
Lee, et al., proposed a method for the preparation of amorphous, anhydrous crystalline, or hydrated crystalline paclitaxel using several solvents (Jeong Hoon Lee, Un-Sook Gi, Jin-Hyun Kim, Yongae Kim, Seon-Ho Kim, Hunseung Oh, and Bumchan Min, Preparation and characterization of solvent induced dihydrated, anhydrous, and amorphous paclitaxel, Bull. Korean Chem. Soc., 2001, 22, 925-928). In this method, the crystalline structure of paclitaxel can be selected by the several applied solvents, but reduced pressure drying and re-crystallization pose numerous problems as follows.
First, in the case of simple reduced pressure drying by Lee, et al., as paclitaxel is dried while being gelled as if it is coated onto a container that is used during the drying process, recovery is very difficult. Also, as the size of particles to be formed is very large, they are still very large at above 100 μm even after recovery and fragmentation. Such a big particle size can be a cause of solubility decrease and make drying difficult while keeping the amount of remaining solvents in an infinitesimal quantity. In medical products used for medical purposes, each solvent should remain below a certain level according to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use), and in the case of drying by methods such as reduced pressure evaporation, it takes considerable time to sufficiently lower the level of remaining solvents because of particle size and the properties of the particles. Further, existing re-crystallization methods have a low yield due to the very nature of the process, they are required to be carried out for a long time at a low temperature, and the size of crystals to be formed is large.